A few aminomethylindans and related compounds are known from the prior art.
So, EP patent 0 281 261 discloses 1-aminomethylindan, 3-aminomthylbenzofurane and 3-aminomthylbenzothiophene derivatives with a hydroxy group or a substituted hydroxy group in the 6-position (indan) or 5-position (benzofurane, benzothiophene). These compounds were found to show central dopamine agonist activity, in particular to show effect at presynaptic dopamine receptors.
GB Patent No. 2 093 837 A relates to a class of 1-aminoalkyl tetraline derivatives having one or more hydroxy or alkoxy substituents in the 5-, 6- and/or 7-position and claimed to show adrenergic and dopaminergic effects, thus being useful in the treatment of hypertension. DeBernardis et al. in J. Med. Chem., 1985, 28 (10), 1398-1404 discuss such effects with respect to dihydroxy-substituted aminomethyltetralines, -indans and benzocyclobutenes.
EP Patent No. 0 402 923 A2 discloses 2,5-diaminotetraline derivatives alleged to have central dopamine agonistic activity, with different compounds interacting with different functional dopamine receptors, thus having different therapeutical effects, such as effects in schizophrenia, hypertension and Parkinsonism.
DE Patent No. 39 24 365 A1 describes a class of 2-amino-7-carbamoyltetraline derivatives said to have presynaptic dopamine agonistic properties, and accordingly antihypertensive and heart rate decreasing effects and effects in the central nervous system.
In U.S. Pat. No. 4,500,543 certain 1-aminomethylphtalane compounds are said to show adrenergic effects and, accordingly, antihypertensive and heart rate decreasing properties. Said patent generically covers compounds having substituents in the 5-, 6- and/or 7-position.
FR Patent No. 2 548 146 relates to 3-aminomethylthiophtalide and 3-aminomethylisobenzofuranethione derivatives claimed to have analgesic and/or anticonvulsive effects.
None of these references discuss or suggest that any of the compounds have 5-HT.sub.1A receptor activity.
Clinical studies of known compounds having 5-HT.sub.1A agonistic activity, such as buspirone, 8-[4-[4-(2-pyrimidyl)-1-piperazinyl]butyl]-8-azaspiro[4,5]decane-7,9-dione , gepirone, 4,4-dimethyl-1-[4-[4-(2-pyrimidyl)-1-piperazinyl]butyl]-2,6-piperidinedion e and ipsapirone, 2-[4-[4-(2-pyrimidyl)-1-piperazinyl]butyl]-1,2-benzothiazol-3(2H)-one-1,1- dioxide, have shown that such compounds are useful in the treatment of anxiety disorders such as generalised anxiety disorder, panic disorder, and obsessive compulsive disorder (Glitz, D. A., Pohl, R., Drugs 1991, 41, 11). Also preclinical studies indicate that compounds with 5-HT.sub.1A agonistic effects are useful in the treatment of the above mentioned anxiety related disorders (Schipper, Human Psychopharm., 1991, 6, S53).
There is also evidence, both clinical and preclinical, in support of the beneficial effect of compounds having 5-HT.sub.1A agonistic activity in the treatment of depression as well as impulse control disorders and alcohol abuse (van Hest, Psychopharm., 1992, 107, 474; Schipper et al, Human Psychopharm., 1991, 6, S53; Cervo et al, Eur. J. Pharm., 1988, 158, 53; Glitz, D. A., Pohl, R., Drugs 1991, 41, 11). 5-HT.sub.1A agonistsic compounds inhibits isolation-induced aggression in male mice indicating that these compounds are useful in the treatment of aggression (Sanchez et al, Psychopharmacology, 1992, in press).
Furthermore, compounds having 5-HT.sub.1A agonistic activity have been reported to show antipsychotic effect in animal models (Wadenberg and Ahlenius, J. Neural Transm, 1991, 83, 43; Ahlenius, Pharm. Tox., 1989, 64, 3; Lowe et al., J. Med. Chem., 1991, 34, 1860; New et al., J. Med. Chem., 1989, 32, 1147; and Martin et al., J. Med. Chem., 1989, 32, 1052).
Recent studies also indicate that 5-HT.sub.1A receptors are important in the serotonergic modulation of haloperidol-induced catalepsy (Hicks, Life Science 1990, 47, 1609) suggesting that 5-HT.sub.1A agonists are useful in the treatment of the side effects induced by conventional antipsychotic agents such as e.g. haloperidol.
Compounds having 5-HT.sub.1A agonistic activity have shown neuroprotective properties in rodent models of focal and global cerebral ischaemia and may, therefore, be useful in the treatment of ischaemic disease states (Prehn, Eur. J. Pharm. 1991, 203, 213).
Both in animal models and in clinical trials it has been shown that 5-HT.sub.1A agonists exert anthihypertensive effects via a central mechanism (Saxena and Villalon, Trends Pharm. Sci. 1990, 11, 95; Gillis et al, J. Pharm. Exp. Ther. 1989, 248, 851). Compounds having 5-HT.sub.1A agonistic activity may, therefore, be beneficial in the treatment of cardiovascular disorders.
Accordingly, compounds having 5-HT.sub.1A agonistic activity are believed to be useful in the therapy of such conditions, and thus being highly desired.